Phenyl esters of t-amcha

ABSTRACT

Compounds of the formula   HAVING ANTI-PLASMIN ACTIVITY HAVE BEEN PREPARED.

United States Patent Yamamura et al.

[451 Oct. 17,1972

PHENYL ESTERS 0F T-AMCHA Inventors:

Assignee:

Filed:

Appl. No.:

Yulchi Yamamura, Osaka; Setsuro Fujii, Tokushima-shi; Atsuji Okano;

Miyoshi Hirata, both of Tokyo; Yasushi Abiko, Matsudo-shi; Masato lnaoka, Funabashi-shi; Reimei Moroi, Chiba-shi; Mashiro Iwamoto;

.Shoichi Funabashi, both of Tokyo;

Takeo Naito, Ichikawa-shi, all of Japan Daiichi Seiyaku Co., Ltd., Tokyo, Japan Sept. 30, 1969 862,512

Foreign Application Priority Data om, 14, 1968 Japan ..43/74220 Dec. 12, 1968 Japan ..43/90564 U.S. Cl ..260/468 R, 260/295 R, 260/468 c,

260/471 A, 260/472, 260/473 S, 260/473 G,

424/266, 424/305, 424/309 [51] Int. Cl..... ..C07c 69/74, C07C 69/78 [58] Field of Search. ..260/468, 471

[56] References Cited Compounds of the formula L0 0 O-P henyl NIL- H2- aving anti-Plasma a'aaaaga .aaaaaa.

10 Claims, No Drawings carboxylic acid (cf. Chemical and Pharmaceutical Bul- 10 letin Vol. 13, 1012-1014 (1965)) and its n-hexyl ester (cf. Japanese Pat. No. 507,331 which corresponds to Japanese Pat. Publn. No. 11059/67 published on June 20, 1967) or benzyl ester (cf. Japanese Pat. No. 526,594 which corresponds to Japanese Pat. Publn. No. 6455/68 published on Mar. 9, 1968) have been known as those having anti-plasmin activity. Among these, t-AMCHA has been used clinically with successful results. However, its n-hexyl and benzyl esters have not been used in practice because of their indistinct effectiveness over t AMCHA and their unfavorable side effect.

We have now found that the new aromatic esters of t- AMCHA and PAMBA are effective many times inantiplasmin activity over t-AMCHA and its n-hexyl' and benzyl esters.

Compounds of the present invention are represented by the general formula:

coo Aryl wherein 0 represents a trans-4-aminomethyl-cyclohexyl or 4-aminomethyl-phenyl group, and Aryl represents an aromatic group selected from phenyl, pyridyl, N-oxide-pyridyl and naphthyl groups which may have one or more substituents. More specifically, the present invention comprehends compounds of the following two groups defined by the formula and wherein Aryl has the same meaning as above.

Compounds of the present invention which are new esters of t-AMCHA and PAMBA are valuable as medicines because of their distinguished anti-plasmin activity. The excellent activity of these esters can be considered owing to the existence of a direct ester linkage of an aromatic ring with the carboxyl group of t- AMCHA or PAMBA, without depending on the type and number of any substituents on said aromatic ring.

Accordingly, the aromatic group which is indicated by the symbol Aryl in the above-referred general formulas may have one or more (i.e. up to three) substituents selected from hydroxy, halogen, nitro, subst. or non-subst. amino, carboxyl, formyl, sulfamoyl, prim.-, sec.- or ter.-alkyl having one to six carbon atoms, alkoxy having l-6 carbon atoms, alkenyl having one to six carbon atoms, phenyl, carboxyalkoxy, carboxyalkenyl, alkoxycarbonyl, carboxyalkylcarbonyl,

i hydroxyalkyl, and carboxyalkyl the alkyl portion of which may be substituted with amino, hydroxy or halogen.

Thus, it should be understood that the term, aryl, used in the specification and claims means to cover 2 phenyl, pyridyL'N-oxide-pyridyl and naphthyl which may be optionally substituted with one or more of the above-said substituents.

The new aryl esters of the present invention can be prepared by the reaction of trans-4-aminomethylcyclohexane-l-carboxylic acid halogenide or 4- aminomethyl-benzoic acid halogenide with an appropriate aryl alcohol. The amino group of these reactants may optionally be blocked by a protective group which is commonly used in a polypeptide synthesis. Such protective group can be easily removed after the intended reaction.

The typical preparation of compounds of the present invention can be illustrated by the following chemical fonnulas:

wherein Q means aforementioned Q itself or that the terminal amino group of which is blocked with such protective group as benzyloxycarbonyl, tert-butyloxycarbonyl and the like, and (Aryl)' means the aforementioned Aryl itself or that in which any amino and/or carboxyl group if present are protected with benzyloxycarbonyl and/or benzyl group, respectively.

These protective group in Q and Aryl can be easily removed in above step of (III) to (IV) by treating under reductive conditions or by hydrogen bromide-acetic acid.

The acid halogenide (I) may be directly reacted with the aryl alcohol (ll) without using any solvent. Alternatively, the halogenide (l) is dissolved or suspended in a suitable inactive solvent such as ethyl acetate, benzene, tetrahydrofuran, dioxane, carbon tetrachloride, etc. and then the aryl alcohol (II) is added to the resulting solution or suspension to effect reaction. The reaction can proceed even at room temperatures. Stirring and heating are effective to have accelerated reaction. Use of an acid-binding agent, e.g., triethyl amine, pyridine or the like organic base, sometimes is recommendable.-

Typical acid halogenides which are suitable as starting materials in this invention include trans-4- aminomethyl-cyclohexane-l-carbonyl chloride, 4- amino-methylbenzoyl chloride, trans-4-N-benzyloxycarbonyl-aminomethylcyclohexanel -carbonyl chloride, trans-4-N-tert.butyloxycarbonylaminomethyl-cyclohexane-l-carbonyl chloride, 4-N- benzyloxycarbonylaminomethyl-benzoyl chloride, 4-N- tert.butyloxycarbonyl-benzoyl chloride, trans-4-N-pmethoxybenzyloxycarbonylaminomethyl-cyclohexanel-carbonyl chloride, etc.

The esterification reaction can be carried out by using a non-protected acid halide as the starting material if the aryl alcohol (ll) used is liquid and the solubility of the resulting ester is sufficient to keep the reaction medium liquid.

However, when the aryl alcohol used is solid and has poor solubility into the organic solvent used, it is preferable to use a protected acid halide as the starting material for esterification, because the said protected acid halide (e.g. N-benzyloXycarbonyl-AMCHA- chloride) has considerable solubility to various organic solvents, while non-protected acid halide has little solubility.

Among these, those compounds in which the amino group is blocked are novel compounds and can be easily prepared by various methods which are known per se. For example, trans-4-aminomethyl-cyclohexane-lcarboxylic acid is brought intoSchotten-Baumanns reaction with benzyloxycarbonyl chloride thereby to obtain trans-4-N-benzyloxycarbonyl-aminomethylcyclohexane-l-carboxylic acid (m.p. ll5-ll7 C.), which is then reacted with thionyl chloride, phosphorous pentachloride, phosphorus trichloride, phosphorus oxychloride or the like chlorinating'agent thereby to obtain hygroscopic crystalline trans-4-N- benzyloxycarbonyl-aminomethyl-cyclohexane- 1 -carbonyl chloride (m.p. 77-7 8 C.).

When the acid halogenide having a protective group in its amino group is employed as starting materials, the compound (lll) thereby obtained have the corresponding protective groups,which should be removed to obtain desired aryl ester (IV).

Removal of theprotective group can be made by any conventionally known method, for example, (a) by treatment of an acetic acid solution of hydrobromic acid, or (b) by catalytichydrogenation in the presence of palladium-carbon, platinum or the like catalyst in the absence or presence of an organic-acid (e.g. ptoluene-sulfonic acid, succinic acid, methane sulfonic acid) or an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid) in hydrogen stream. When the hydrobromic acid-acetic acid solution is used, the intended reaction is conveniently carried out in the 5-35 percent hydrobromic'acid solution at a temperature from room temperature to 100 C.

The procedure (a) is recommendable when only the ,acyl group for blocking amino group is to be removed with retaining any reduction-susceptible group (e.g. nitro, formyl, vinyl, etc.) on the aryl portion derived from the aryl alcohol reactant. If reduction of the reduction-susceptible group also should be effected simultaneously withremoval of the protective group, the catalytic hydrogenation (b) using palladium or platinum is recommendable.

As apparent from the above description, various steps can be taken suitably, depending on the type of desired aryl ester. It is appreciated that the most essential aspect of the present invention resides in finding of highly distinguished anti-plasmin activity of certain new aryl esters. However, it also is to be noted that another aspect of the invention resides in the preparation of the said aryl esters by the reaction of trans-4- aminomethyl-cyclohexane-l-carbonyl halogenide or paminornethylbenzoyl halogenide with an appropriate aryl alcohol, whereas the introduction or removal of a protective group and the reduction or conversion of any aryl substituted on are mere modifications of the invention which are obvious to those skilled in the art.

The thus obtained aryl esters'of trans-AMCHA and Pamba can be isolated in the conventional manner known per se. Usually, it is recommendable to recover these aryl esters in the form of their acid addition salts. Suitable salts are hydrochloride, hydrobromide sulfate, nitrate, phosphate, sulfonate, methanesulfonate, citrate, etc. Hydrochloride and methanesulfonate are particularly preferred because of their utility in medicinal applications.

' trans-AMCHA are several ten times more potent than The aryl esters and their pharmaceutically acceptable acid addition salts comprehended by the invention are useful as medicines because of their high antiplasmin activity and their good stability in blood. Particularly useful are the substituted phenyl. esters of t- AMCHA and PAMBA, the substituted phenyl portion of which is 4'-carboxyphenyl, 4'-carboxymethylphenyl, 4 -(2-carboxyethyD-phenyl. 4' -(2f'- car b@r yvinyl): phenyl, 4'-(5"-carboxyethoxy)-phenyl, 4-(5"-carboxy-n-pentyl)-phenyl, 4-( 1 '-hydroxy-5 '-carboxy-n-pentyl)-phenyl, 4-( l "-oxo-S"-carboxy-n-pentyl)-phenyl or 4'-(2-arnino-2"-carboxyethyl)-phenyl. Their pharmaceutically acceptable acid addition salts also are preferred.

Anti-plasmin activity of these new aryl esters is assayed by either of the fibrinolytic or caseinolytic method. In the caseinolytic method, the aryl esters of trans-AMCHA inhibit the plasmin activity several hundred times or several ten times more strongly than trans-AMCHA or 'benzyl -trans-4-aminomethylcyclohexanecarboxylate, respectively, does.

Anti-fibrinolytic activities of these aryl esters of those of 'trans-AMCHA or benzyl trans-4a aminomethyl-cyclohexanecarboxylate. The aryl esters of PAMBA, also possess high anti-fibrinolytic and anticaseinolytic activities which are several times more potent in the former and several ten to hundred times As apparent from the data of TABLE 1 and TABLE 2, the new aryl esters of trans-AMCHA an'd PAMBA leap into several ten to hundred times more potent in their activities. Although the reason why the aryl esters of the invention can show markedly high pharmacological activities is not fully clear still yet, it is believed that the esters of the invention in which aromatic ring is directly linked to the carboxyl group of the t-AMCHA or PAMBA portion are more effective in anti-plasmin activities than the known benzyl esters in which the aromatic ring is connected through a carbon chain with the carboxyl group.

-The aryl esters of trans-AMCHA and PAMBA strongly inhibit the action of plasmin itself as well as the activation of plasminogen to plasmin, whereas it has been reported that trans-AMCHA and PAMBA inhibit only the activation of plasminogen to plasmin (S. Okamoto and U. Okamoto, Keio J. Med. (Tokyo), 11, (1962); A.H.C. Dubber et al., Brit. J. Haematol., 11, 237 (1965); M. Maki and F. K. Beller, Thrombos. Diathes. Haemorrh., 16, 668 (1966); F. Markwaldt et al., Z. Physiol. Chem., 340, 174 (1965); and European J. Biochem., 6, 502 (1968)).

In addition to their superiority in inhibiting the plasmin activity, these aryl esters of trans-AMCHA possess marked inhibitory actions on blood coagulation system including thrombin, on trypsin and on kalif' l j 428 424 likrein. These inhibitory actions are not found or are very little in the previously known antifibrinolytic ig-v 970 agents, such as trans-AMCHA, e-aminocaproic acid, g g 6 3 M3 905 77 PAMBA and benzyl trans-4-aminomethylcyclohex- 5 p-carboxymethanecarboxylate gl-(pzhggtyllmnh W0 80 89.3 66.7 53.8 Compounds of the invention which possess inhibitoelhyl)-phenyl 126 135 56.8 70 77 ry actions on the fibrinolytic, blood clotting and kinin- 44 2 43 2 27 8 2 6 forming systems may be useful for the treatment of various hemorrhage (caused by defibrination) which y l-p y I98 226 162 215 will be observed in the primary hyperfibrinolysis and 7 even in the secondary hyperfibrinolysishomeostatically phenyl 86.0 80.2 23.8 33.1 28.9 following intravascular coagulation state. Anti-trypsin' Pa 8 m 58 7 and anti-kallikrein activities of these compounds also 61 support their clinical utility in the treatment of acute l5 pen!yl)-phenyl 200 254 171 223 pancreatitis. lglygroxyfi 9 TABLE 1 53111131123? rboxy-pentyl)- Relative activities of esters of trans-A-MCHA and 53mg, (28 is? v I I I PAMBA pyridine N- oxide-3-yl 33 14s Aryl. 'a-naphthyl 68 8.8 Anti-Plasmin Anti- Anti-Plasmin B-naphthyl 87 C as- Fibrin thrombin Casein Fibrin 3. -b .2. I m naphthyl. 9 14.8

TABLE 2.OONCENTRATION OF DRUGS CAUSING INHIBITION Anti-plasmln F Casei- Fibri- Anti- Antinolysis nolysis thrombin 'Irypsin Anti-kalllkrein trans-AMCHA 2,400 (1) 49 (1) Inact1ve. Inactive Inactive. PAMBA 4,000 (0.6) 110 (0.54) d0 Very k D0. Benzylester of 56 (43) 37 (1.6) 600 (1) 2483 Do. riifir i ll r o r 2 1,200 1.8 (32.8) 5 (100)- 50 (4.s Less than 1,000.

pfiiifi hiyfii 12 (200 9 (6.6)

PAMBA.

(Figures in the parenthesis indicate relative activities.)

v 2g gg 4 2g LEGEND FOR TABLE 2 O-lO U mmluyyl 501 1. The concentrations are represented as umoles/m]. 'ijifl ii 173 7L5 45 2. Anticaseinolytic activity of the compounds was Phenyl v 61 determined by the method of M. Shimizu, et al. [Chem. m 63 Pharm. Bull. (Tokyo), 16, 357 (1968)]. 0.5 ml of py euglobulin solution prepared from human blood was gi f 'g 416 50 preincubated with 1 m1 of 2% casein solution in methylphenyl 96.5 phosphate buffer-saline (pH 7.4) and 0.4 ml of the 233 260 phosphate buffer-saline containing various amounts of o-chloroan inhibitor to be tested at 37 C. for 3 minutes. Then, P y 162 0.1 ml of streptokinase solution (200 units) was added 3 :2? 136 853 250 34,8 55 and the mixture was incubated at 37 C. for 20 minutes. After incubation, 2 ml of 17 percent perchloric acid g i'g 250 250 was added, allowed to stand at room temperature for phenyl 140 200 159 about 1 hour, and centrifuged. The extinction of the flmg if 97 clear supernatant was measured at 280 my. against an 511 l y 149 171 163 60 enzyme blank to which the streptokinase solution was L 74 3 96 5 94 4 added after the addition of perchloric acid. The inhibi- 553 tion rates were calculated by comparison with the cony -p 172 169 trol run which contained no inhibitor.

I ,3? 2; I 3. Antiiibrinolytic activity was determined according to o-nitro-p 65 the method of S. Okamoto and U. Okamoto [Keio J. igw Med. (Tokyo), 11, 105 (1962)]. 0.1 ml of the human phenyl 49 323 euglobulin solution was mixed with 0.5 ml of the and finally 0.2 ml of 0.5 percent bovine fibrinogen solution in phosphate buffer-saline was added to the above mixture. The lysis time of the fibrin clot formed was.

measured at 25 C. after the addition of fibrinogen. 1nhibitory actions of the compounds are represented as the concentrations of the compounds for doubling the clot lysis time of the control run which contained no inhibitor.

4. Anti-thrombin activity of the compounds was determined by the fibrin-clot forming reaction due to thrombin. Inhibitory actions of the compounds are represented as the concentrations of the compounds for doubling the clotting time of the control run which contained no inhibitor. 5. Anti-trypsin activity of the compounds were determined by the caseinolytic reaction due to trypsin.

6. Anti-kallikr'ein activity of the compounds was deter mined by the kinin-forming' reaction due to human plasma kallikrein activated with acetone followed by l tinin bioassay using isolated guinea pig uterus or by the. esterolytic reaction of a N-tosyl-L-aiginine methylester due to plasma kallikrein.

Compounds tested Toxicities. L DMmg/kg) Aryl C,H,, 119.7 (LV. mouse) p-O,N-C,H 200 (LV. mouse) p-HOOC-ClL-CJL- 1097 (LP. mouse) p-HOOC-CH= CH-C,,H 1062 (LP. mouse) 850 (LP. rat), 480 (LV. mouse), 6000 (P.O. mouse) 409 (l.V. mouse), 9080 IN .zlntra-venous administration. l.P.:lntra-peritoneal administration. P.O.:Per os Now the following examples will be given to show the present invention in detail.

EXAMPLE 1 2.5 g (0.011 mole) of 4-benzyloxycarbonylphenol and 1.2 g of triethylamine were dissolved in 20 ml of dried tetrahydrofuran. To this solution was added 3.1 g (0.010 mole) of trans-4-N-benzyloxycarbonylaminomethyl-cyclohexane-l -carboxylic acid chloride dissolvedin 10 ml of dried benzene. The mixture was stirred for about one hour at room temperature, heated to 80 C. for 30 minutes and then evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed several times with water, dried and evaporated to obtain colorless syrup. After cooling, thesyrup changed to solid, which was recrystallized from ethanol to obtain 4.9 g 88 percent)v of '4-benzyloxycarbonylphenyl trans-4-N-benzyloxycarbonylamino- 'methylcyclohexane-l-carboxylate with a melting point of98-100C. v

2.5 g (0.005 mole) of this ester was dissolved in 10 ml of tetrahydrofuran and 20 ml of methanol. To this solution were added 2 ml of 25 percent methanolic hydrochloric acid and 0.5 g of palladium on carbon. The mixture was treated with hydrogen stream under an atmospheric pressure at room temperature. After the absorption of the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated in vacuo at low temperature to obtain white crystals. Recrystallization of the crystals from ethanol yielded 1.0 g percent) of 4'-carboxyphenyl trans-4- aminom ethyl-cyclohexanel -carboxylate hydrochloride in the form of prisms with a melting p;oint of 255 C. (decomposed).

1 Elementary analysis for C, H, O NCl:

313.78) Calcd. C 57.41, H 6.42, N 4.46, Cl 11.30 Found C 57.28, 116.39,}1 4.61, Cl 10.79

EXAMPLES 2-10 By repeating the substantially same procedures as in- P- olest Example 1, various new aryl esters were prepared. The results are summarized in the following Table 3.

Table 3.NH2OH2@- -0 0 O-Aryl Yield Elementary analysis (found) 1 Example M.p. (per number Aryl Salt C.) cent) 0 H N C1 a (:1 H01 210-213 (dec.) 78.3 45.31 4. 42 4.06 38.10

4 CH3 HCl 241 (dec.) 78 64.73 s. 14 4.81

Table 3.-NH2CH2@ -c O-Aryl- 0611 111611 Exam le p Salt Elementary analysis (found) benzyloxycarbonylaminomethylcyclohexane-l-carboxylate was prepared by reacting methyl 3-nitro-4- hydroxybenzoate with trans-4-N-benzyloxycarbonylaminomethylcyclohexanel -carboxylic acid chloride number Aryl 0 11 N 01 l 5 CH3 H01 221-223 ((180-) 68 64.65 6.04 5.07

11.. (13H: HCl 256 ((180.) 86 66.48 8.63 4.86

- --e-oH1 7' on n01 212-214 (1166. 42 59.17 7.59 4.66

14.. 00011 HCl 181-183 (1166. 40 52.69 5.81 3.93

- cooH%H2- 11 21101 262 (dec.) 52.50 6.88 8.97 NH2 1 I I 10 00Ha H01 1821-1916146.) 46 60.44 7. a7 4.79.

EXAMPLE boxylate hydrobromide in the form of prisms with a 30 melting point of l83-l86 C. 2'-Nitro-4-methoxycarbonylphenyl trans-4-N- Elementary analysis for C l-I O N Br:

Calcd. c 46.05, 11 5.07, N 6.71 Found c 46.24, 11 4.94, N 6.57

EXAMPLES 12-16 By repeating the substantially same procedures as in Example 1 1, various new aryl esters were prepared. The results are summarized the following Table 4.

EXAMPLE l7 v 2.0 g of benayl 4-hydroxycinnamate and 1.0 g of Example M.p.

Yield number Aryl Salt (percent) C H N Br 12 HBr 190-192 (dee.) 46. 82 5. 57 7. 67

13 0 CH HBr 242-245 (dee) 76 62. 02 6. 28 3. 66

- CHO 14 HBr 261 (dec.) 86 42:53 5.43 7.23 20. 67

S OgNHz 15 i 2HB1 193495 (doc) 52. 2 39. 27 5. 01 7. 4 1 39. 93

16 )0 HBr 278 (11%.) 58 46. 93 5. 79 8. 54

obtain 1.2 g (56 percent) of 2'-nitro-4'-methoxycarbonylphenyl trans-4-aminomethylcyclohexane-l cartriethylamine were dissolved in 10 mlof dried dioxane. To this solution was added 2.5 g of trans-4 N-benzyloxcent) of 4'-(2"-benzyloxycarbonylvinyl)phenyl trans-' 4-N-benzyloxyc arbonylaminomethylcyclohexanel carboxylate in the formof white crystalline powder with a meltingpoint of 12 l-l 23 C.

Elementary analysis for C H O N (M.W. 527.62):

Calcd. C 72.82, H 6.30

Found C 72.23, H 6.15

To this ester was added .20 g of 33 percent hydrobromic acid solution in acetic acid. The mixture wasstirred for about 20 minutes at room temperature.

Then the mixture was cooled enough and then added with 50 ml. of dried diethyl ether. The crude product precipitated was collected by filtration, washedwith diethyl ether and recrystallized 'from ethanol-diethyl boxy late hydrobromide in the form of white crystalline powder with a melting point of 252-254C. (dec.).

Elementary analysis for C -,H,,O,NBr (M.W;

384.27) Calcd. C 53.13, H 5.77, N 3.64, Br 20.80

Found C 53.07, 6.29, N 3.7 l Br 20.84

EXAMPLES 18-19 EXAMPLE 20 4-N'-(2"-benzyldxycarbOnylamino-Z"-benzyloxycarbonylethyl)phenyl trans-4-N-benzyloxycarbonylaminomethyl-cyclohexane-l-carboxylate with a meltbenzyloxycarbonylaminomethyl-cyclohexane- 1 -carboxylic acid chloride in the same manner as in Example 4.5 g of the obtained ester was dissolved in 30 ml of glacial acetic acid, and to the resulting solution 0.5 g of 10 percent palladium-on carbon was added. The mixture was treated with hydrogen stream under an atmospheric pressure at room temperature. After the absorption of the theoretical amount of hydrogen, the catalyst was filtered off. By adding 5 percent hydrochloric acid in acetic acid, diethyl ether and petroleum, ether to the filtrate, crude product was precipitated andthen collected by filtration. The crude Elementary analysis for C H,,O,N,'2HCl (M.W. ...3 ..-l);

Calcd. C 51.91, H 6. C 5

66, N 7.12, c11s.03 1. 5. 1. 1

EXAMPLES 21-30 35 By repeating the substantially same procedures as in Example 20,various new aryl esters were prepared. pit .atssummarizeslimhsi ns'febl TABLE 5 40 Elements anl sis found. Example M.p. Y1 number Ary1 Salt 0.) (percent), 0 H N Br 18 1131' 210 (dec.) 51.98 5.94 4.16 20.69

I'IBr (dee) 66 65.60. 6.76

' (CI-Ia)sCOOI-I Table e. Nmcm-@---- c o O-Aryl Example Yield number Aryl Salt M.p. C.) (percent) C H N Cl Br 8 21 NH; 2HBr 2011-2010190.) 92.4 41.13 6.58 5.715 32.76

Q-cmbnooon 22 NH: zcmsotH 204-206(dec.) 43.33 6.54 5.55 11.87

Q-ombnooon-mo 23 H61 236-238(dec.) as 59.89 6.91 4.08

Q-cmorncoon 'onasorrr 213-2111 so 53.76, 6.64 11.38 s09 Q-CmCmOQQH Elementary analysis (found) product was recrystallized from ethanol-ether to obtain ne-l-carboxylate (prepared in Example 17) was treated in the same manner as in Example to obtain 1.8 g (87 percent) of 4-(2"-carboxyethyl)phenyl trans-4-aminomethylcyclohexane- 1 -carboxylate hydrochloride in the form of white crystalline powder with a melting point of 236-23 8 C. (dec.).

EXAMPLE 32 12.4 g (0.04 mole) of trans-4-aminomethylcyclohexane-l-carboxylic acid chloride was dissolved in 50 ml of benzene. The resulting solution was added dropwise to a solution of 5.4 g (0.044 mole) of 4- hydroxybenzaldehyde and 6.4 g (0.08 mole) of pyridine in 20 ml of dioxane at room temperature, and allowed to stand overnight. After the removal of pyridine hydrochloride by filtration, the filtrate was evaporated to dryness in vacuo. To the residue water and benzene were added, and then the benzene layer was washed enough with water, dried and evaporated to dryness in vacuo to obtain colorless crystals. Recrystallization of the crystals from ethanolpetroleum-ether yielded 10 g (62.5 percent) of 4'-forrnylphenyl trans-4-N-benzyloxycarbonylaminomethyl-cyclohexane-l-carboxylate in the form of powder with a melting point of l05- 107 C.

Elementary analysis for C l-l O N (M.W. 395.44):

Ca1cd.C 69.85, H 6.37, N 3.54

Found C 70.01, H 6.29, N 3.65

10 g of this ester was dissolved in ml of tetrahydrofuran and then 60 ml of methanol was added. To the solution 0.5 g of sodium borohydride was added with cooling with ice water and the mixture was stirred for one hour. When the mixture was poured into cold water, white crystals were precipitated. The crude crystals were washed with water, dried and recrystallized from ethanol and further from ethanol-petroleum ether to obtain 6.3 g (64 percent) of 4-hydrox- Tnblt) 0.NIIzCI1'2- I 0 o O-Aryl ,nmnmmu Elementary nlmlysls (found) Example Ylold number Aryl Salt M.p. 0.) (percent) C II N Cl Br 5 26 cmomoooH H01 197-199 81.3 9. 77 6. 98 4.17 10. 76

26 H01 213 (dec.) 84.3 57.03 6. 70 4. 26 10.55 OCHOH1COOH 27 H01 173-175 62 60. 14 7. 17 3. 61 8.95 CO(CH2)4COOH NH 0H10 0 OH 'COOH 30; N HCl 216-218 ((180.) j 40 52.19 6. 0:1 8.45 10.64 COOH v v EXAMPLE 31 ymethylphenyl trans-4-N-benzyloxycarbonylamino- I meth 1 c1 3.2 g of 4-(2"-benzyloxycarbonylv1nyl)phenyl dles a f if g i f fga fgfi T form of nee trans-4-N-benz lox carbon laminometh 1c clohexa y y y y y 30 Elementary analyslsfor C H -,O N (M.W. 397.45):

Ca1cd.C 69.50, H 6.85, N 3.52

Found C 69.37, H 6.90, N 3.62

6.3 g (0.016 mole) of the ester was dissolved in 150 ml of methanol. To the resulting solution were added 2 g of 30 percent methanolic hydrochloric acid and 3 gotpalladium on carbon. The mixture was treated with hydrogen stream under an atmospheric pressure at room temperature. After the absorption of the theoretical amount of hydrogen the catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The white residue was recrystallized from methanol-diethyl ether to obtain 2.5 g (52 percent) of 4'-hydroxymethylphenyl trans-4-aminomethyl-cyclohexanelcarboxylate hydrochloride in the form of white needles with a melting point of 24l-242 C. (dec.).

Elementary analysis for CI5H22O3NCI 299.81): Calcd. C 60.09, H 7.39, N 4.67, Cl 1 1.82 ou qqw-zi. 11 .81 1.479.911. 7

EXAMPLE 33 trans-4-N-benzyloxycarbonylaminomethylcyclohexa cyclohexane-l-carboxylate with a melting point of I 62- 65 C. Yield 79 percent.

Elementary analysis for C H41NQ1 (M.W. 587.69); v Calcd.C71.53,l-l7.03,N2.38

The above-resulted compound was treated in the same manner as in Example 20 to obtain 4'-(l"- hydroxy-S -carboxy-n-pentyl-)phenyl trans-4- aminomethylcyclohexane- 1 -carboxylate hydrochloride in the form of prisms with a melting point of l50-154 10 C. Yield 53 percent.

Elementary analysis 399.91): v Calcd. C 60.06, H 7.56, N 3.50, C] 8.87

for 11 0 1401 (M.W.

FoundC60.l5,l-l7.56,N3.76,Cl9.37

EXAMPLE 34 4'-( l '-hydroxy-5 "-benzyloxycarbonyl-n-pentyl)phenyl trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate obtained in Example 33 was treated with hydrobromic acid-acetic acid in the same manner'as in Example ll to obtain 4'-(l"- bromo-S '-carboxy-n-pentyl)phenyl trans-4- aminomethylcyclohexane- 1 -carboxylate hydrobromide in the form of powder with a melting pointof 139 C. (dec.). Yield 39.4 percent.

Elementary analysis for C l-l O NBr (M.W.

507.27): Calcd. C 47.35, H 5.76, N 2.76, Br 31.51

Found C 47.31, 11.5.90, N 3.02, Br 30.92 7

EXAMPLE 3 5 Trans-4-N-tert-butyloxycarbonylaminomethylcyclohexane-l-carboxylic acid chloride in the form of 35 syrup prepared by reacting 2.3 g of trans-4-N-tertbutyloxycarbonylaminomethylcyclohexanel -carboxylic acid with 2.4 g of thionyl chloride in the presence of triethylamine was dissolved in 40 rnl of dried benzene.

washed enough with water, dried-and evaporated to dryness. The residue was recrystallized from ethyl acetate-petroleum ether to obtain 3.1 g (63.0%) of 4'- (2"-benzyloxycarbonylvinyl) phenyl trans-4-N-tert-butyloxycarbonylaminomethylcyclohexane- 1 -carboxylate in the form of small'needles with a melting point of Elementary analysis for CC H O N (M.W. 493.5 8):.

Calcd. C 70.56, H 7.15, N 2.84

Found C 70.22, H 6.59, N 2.99

The thus obtained compound was treated in the same manner as in Example 17 to obtain 4'-(2"-carboxyvinyl)-phenyl trans-4-aminomethylcyclohexane- 1 -carboxylate hydrobromide in the form of white crystalline powder with a melting point of 252-254 C. (dec.). Yield 68 percent.

EXAMPLE 36 To 4.2 g of trans-4-aminomethylcyclohexane-l-car- EXAMPLES 37-40 By repeating the substantially same procedures as in Example 36, various new aryl esters were prepared. The results are summarizedin the following Table 7.

C14H2oOzNCl TABLE 7.NH2CH2- H C O O-Aryl Elementary analysis (found) Example Yield Number Aryl Salt M.p. 0.) (percent) C H N C1 37 C1 H01 198-202 (dec.) 2 86 56.21 6.42 23.14

as H01 200 203 )dec.) 75 e5. 66 e. 96 4. 51

39. H01 239 @450.) I 62 66. e7 6. 92 4. 42

4o Q H01 243(dec.) 66 69.15 7.03 4.53

To the resulting mixture were added 1.5 g of EXAMPLE 41' triethylamine and 2.6 g (0.01 mole) of benzyl 4- hydroxycinnamate dissolved in 20 ml of dried benzene. The solution was heated to 70-80 C. for minutes on a water bath.After cooling the benzene layer was To 3.0 g of trans-4-aminomethylcyclohexane-l-car boxylic acid chloride hydrochloride, 10 ml of o-cresol was added to occur exothermic reaction. The resulting mixture was allowed to stand for about 30 minutes at room temperature and the crystals were precipitated with a large amount of diethyl ether. The crystals were washed enough with diethyl ether to remove cresol,

and recrystallized from methanol-diethyl ether to obtain 3.2 g (81 percent) of -2-methylphenyl trans-4- aminomethylcyclohexane- 1 -carboxylate hydrochloride in the form of white leaflets with a melting point of 'l8l-l83C.

Elementary analysis for C, ',l-l O NCl (M.W.

283.79): Calcd. C 63.48, H 7.81, N 4.94 Found C 63.36, H 7.71, N 5.23

EXAMPLES 42-49 1 By repeating the substantially same procedures as in Example 41, various new aryl esters were prepared. The results are summarized in the following Table 8.

room temperature in the presence of 0.5 g of 10 percent palladium on carbon. After absorption of the theoretical amount of hydrogen, the catalyst was fil- ;tered.'off, and to the filtrate a large amount of diethyl ether was added. The crude product precipitated was collected by filtration and recrystallized from ethanoldiethyl ether to obtain 1.34 g (79%) of 4-(2"-carboxyethyl)phenyl trans-4-aminomethylcyclohexane- 1 -carboxylate hydrochloride in the form of white crystals with a melting point of 236 -238 C.

Example M.p. 0)

Yield Elementary analysis (found) To 2.1 g of trans 4-aminomethylcyclohexane-1-car- 55 aminomethylcyclohexane- 1 -ca rboxylate hydrochloride H number -Salt (percent) C H N C1 42 oom I HCl 212-213 77 50.43 7.35 4.72;

43 HCl 215-217 (dec.) 83 60.48 7.39 11.51

44 CH3' H01 183-185 79 63.44 7.75 5.07

45; H Cl 240-242 (195. ss 63. 45 7. 53 5.

c1 H01 175-177 s5 55.40 5.11 23.32

47. I o1 I HCl 191-194(dec.) so 55.47 6.84 23.52

43 H01. 159-171 83 47.81 5.35 4.35 49 CH3 H01 215 11%.) 85 64. 64 8.08 5. 02

EXAMPLE 5O EXAMPLE 51 16.6 g (0.1 mole) of 4-hydroxyphenylpropionic acid and 15.8 g of pyridine (0.2 mole) were dissolved in ml of dry dioxaneQ To the mixture, trans-4-N-benzyloxy-carbonylaminomethylcyclohexane-l-carbonyl ghloride dissolygd in m1 of dry benzene was added,

60 and the resulting mixture was stirred for 30 hours at room temperature. Then the precipitated crystals were filtered off and the'filtrate was allowed to stand overa hydrochloride.

hydrogen, the catalyst was filtered off and to the filtrate a small excess amount of hydrochloric acid-acetic acid was added and further dry ether was added. The white crystals were collected by filtration and recrystallized from ethanol-diethyl" ether to obtain 1.28g (82 percent) of 4'-(2"-carboxyethyl)phenyl trans-4- aminomethylcyclohexane- 1 -carboxylate hydrochloride in the form of white crystals with a melting point of 236-238 C. (dec.).

EXAMPLE 52 19 g (0.1 mole) of sodium 4-hydroxypheny1- propionate was suspended in 120 ml of dry dioxane. To the mixture was added 31 g (0.1 mole) oftrang l' N- ;to solid, which was recrystallized from ethanol to obtain 3.1 g (76 percent) of 4-nitrophenyl 4-N-benzyloxycarbonyl'aminomethylbenzoate in the form of yellow needles with a melting point of l43- 145 C. I

Elementary analysis for c n ons, (M.W. 406.38): Calcd. C 65.02,"1-l"4.46, N 6.89 Found C 65.27, 1-l 4.52, N 6.73 2.0 g (0.005 mole) of this ester was dissolved in 10 ml of 20 percent hydrobromic acid-acetic acid. The

solution was warmed to about C. for 10 minutes,

and cooled. Crude crystals were precipitated with ml of drieddiethyl ether, washed enough with diethyl ether andrecrystallized from ethanol to obtain 1.4g

(79 percent) of 4Y-nitrophenyl-4-aminomethy1benzoate hydrobromide in the form of needles with a melting P i ts2i19299-,

Elementary analysis for C l-1 0,N Br (M.W.

Calcd. C 47.61, H 3.71, N 7.93 Found C 47.47, H 4.27, N 7.89

EXAMPLES 54-55 Elementary analysis (found) iflfigf Aryl Salt M-p. 9 o. e t i. o H

54 CH3 HBr 231(dec.) 83 57.41 6.60 4.41

c1 HBr 235(dec.) 64

benzyloxycarbonylamlno-methylcyclohexane- 1 -car- EXAMPLE 56 boxylate dissolved in 150 ml of dry benzene and the resulting mixture was stirred for. 12 hours at room temperature. Then the precipitation was filtered off and the filtrate was evaporated. To the resulting solution 100 ml of diethyl ether was added and the mixture was allowed to stand overnight. The crystals were collected by filtration and recrystallized from ethyl acetatepetroleum ether to obtain 4 g )9.1 percent) of 4'-(2"- carboxyethyl)phenyl trans-4-N-benzyloxycarbonylamino-methylcyclohexane-l-carboxylate in the form of white crystals with a melting point of l02- 105 C.

The ester was treated in the same manner as in Example. 51 to obtain 4'-(2"-carboxyethyl)phenyl trans- 4-aminomethylcyclohexane-l-carboxylate EXAMPLE 53 1.5 g (0.011 mole) of 4-nitrophenol and 1.2 'g'(0.0l2 mole) of triethylamine were dissolved in 20 ml of dried tetrahydrofuran. To the resulting mixture was added 3.0 g (0.01 mole) of 4-N-benzyloxycarbonylaminomethylbenzoic acid chloride dissolved in 20 ml of dried benzene. The mixture was heated to -80 C. for one hour with stirring and evaporated in vacuo. The residue was dissolved in ethyl acetate and the mixture was washed several times with water and evaporated to obtain colorless syrup. After cooling the syrup changed 3.2 g of 4'-rnethoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate in the form of white crystals with a melting point of l25- 127 C. was prepared by reacting 1.4 g (0.011 mole) of 4-methylphenol with 4- benzyloxycarbonylaminomethylbenzoic acid chloride. Yield 82 percent.

Elementary analysis for C 1-1,,O N (M.W. 391.41

Calcd. C 70.57, H 5.41, N 3.58

Found C 70.82, H 5.49, N 3.41

2.0 g (0.005 mole) of this ester was dissolved in 10 -ml of tetrahydrofuran and 20 ml of methanol. To the palladium on carbon. Then the mixture was treated Found 61.94, 115.25, N 4.88

EXAMPLES 57-64 By repeating the substantially same procedures as in Example 56, various new aryl esters were prepared.

The results'are summarized in the following Table 10.

TABLE 10.NH CHz-C o O-Aryl 1.5 g (0.011 mole) of 3-nitrophenol was reacted with 4-N-benzyloxycarbonylaminornethylbenzoic acid chloride to obtain colorless syrup, which was used without purification. The syrup was treated with palladium on carbon in the same manner as in Example 56.

Recrystallization of the crude product from aceton- 1 EXAMPLE 66 4.1 g (0.01 mole) of benzyl N-benzyloxycarbonyltyrosinate and 1.2 g of triethylamine were dissolved in 20 ml of dried benzene. To the resulting solution was added 3.0 g (0.01 mole) of 4 -N-benzyloxycarbonylamino-methylbenzoic acid chloride dissolved in 20 Elementary analysis (found) Example Yield number Aryl Salt M.p. 0.) (percent) 0 H N 51 CH3 H01 220 (1166.) 84 65.85 6.08 4.88

1 1101 244 (dec.) 04 68. a. 29 4. 4s

59 CH5 HCI 246 (666.1 15 67.63 6.89 5.01

.60 OCH; HCl 176-179 60.89 5. 69

61 01 HCl 212-215 56.61 4.51

03 131' HCl 228-231(d90.) 49.25 a 3.82 4.29

EXAMPLE 65 acetate-isopropyl ether yielded 6.0 g percent) of 4'-(2"-benzyloxycarbonylamino-2"-benzyloxycarbonylethyl)phenyl 4-N-benzyloxycarbonyl-aminomethylbenzoate with a melting point of l50- 1 53 C.

Elementary analysis for C H O N (M.W. 672.70): Calcd.C7l.4l,H5.39,N4.l6 Found C 71.83, N 5.32, N 4.14 3.4 g (0.005 mole) of the ester was dissolved in 30 ml of glacial acetic acid. To the resulting solution 0.5 of palladium on carbon was added. The mixture was treated with hydrog en stream at room temperature under an atmospheric pressure. After absorption of the theoretical amount of hydrogen, the catalyst was filtered off. To the filtrate 5 g of 5 percent hydrochloric acid-acetic acid was added. The crude product was precipitated with diethyl ether and petroleum ether, collected and recrystallized from methanol-diethyl ether to obtain 1.2 g (60 percentlof 4'-(2"-carboxy- 2"-amino-ethyl)-phenyl 4-aminomethylbenzoate dihydrochloride in the form of needles with a melting point of 276 -279 C. (dec.).

Elementary analysis for CnHgoNgClg (M .W. 387.28):

Example 66, various new esters were prepared. The results are summarized in the following Table l 1.

TABLE 11.-NH.-@-o O-Aryl benzoate with a melting iiHi'f 108 C.

The ester was reduced with sodium borohydride to obtain 4'-hydroxymethylphenyl 4-benzyloxycarbonylamino-methylbenzoate with a melting point of Then the above-resulted treated with hy 9.99a in the v s sme $191 .9

Elementary analysis (found) EXAMPLE 73 I 3.4 g of 4'42 imtzgiaatagba uva l1.992.191 4 benzyloxycarbonylaminomethylbenzoate in the form of small needles with amelting point of 145"- 1 47 C. was

prepared by reacting 2.5 g (0.0l mole) of benzyl 4- benzyloxycarbon- I hydroxycinnamate with ylaminomethylbenzoic acid chloride. Yield 65 percent.

Elementary analysis for C H O N (M.W. .521 .54):' Calcd. C 73.69, H 5.22, N 2.68 Found C 74.25, H 5.30, N 2.85 2.5 g (0.005 mole) of the thus obtained ester was treated with hydrobromic acid-acetic acid in the same manner as in Example 53 and the resulting product was recrystallized from methanoldiethyl ether to obtain 1.6 g: (83 percent) of '4--(2-carboxyvinyl)phenyl 4- aminomethylbenzoate hydrobromide in the form of prisms with a melting point of 273 C. (dec.).

Elementary analysis for C,-,l-l O.,NBr' 1 [21-1 0 (M.W.

337.23 Calcd. C 52,73, H 4.43, N 3.62 Found C 52.58, H 4.78, N 3.61

EXAMPLE 74 4- Hydroxybenzaldehyde was. reacted with 4-N- benzyloxycarbonylaminoinethylbenioic acid chloride in the same manner as in Example 32 to obtain 4- formylphenyl Example M.p. Yield number- Aryl' Salt 0.) (percent) 0 H I N 01 07 H01 277-279 (dec.) 91 59.22 4.50 4. 77 1 as HCl 260-262 (dec.) s1 59. as a. 04 4. 4o

69-- 1 H01 245-247 (dec.) 83 61.00 6.29 4.22

CHzCHzCOOH 70 7 I 0H,0H,000H H01 234-236 (dec.) '79 60.39 6.16 4. 52 10.82 I

71 f H01 277-279 (dec.) 85 64.76 5.29 3.82

. (CH2)5COOH 72 HCl 240-242(dec.) 74.6 5200 5.02 4.18 10.4.9

inthesa au99r..as.i2.;5s9mvl9: to Obtain hydroxymethylphenyl 4-aminomethylbenzoate d deiq hq5959.929991921912.H??? 1.1.- Elementary analysis for 0,,H,,0,N01 (M.W.

' 293.76): 1 Calcd. C 61.33,.H 5.49, N 4.76 1 Found C 61.62,]! 5.27, N 4.58

, EXAMPLE 75 tain 4.5 g (86 percent) of phenyl 4-aminomethylbenzoate hydrochloride in the form of white powder with a melting point of 248 C. (dec.).

Elementary analysis for C,.H,;0,N01 263.72):

' Calcd. C 63.75, H 5.35, N 5.31

Found C 63.99, H 5.44, N 5.39

v EXAMPLES 76-80 Ey repeating the substantially same procedures as in Example 75, various new aryl esters were prepared.

' 4-N-benZylotycarbonylaminomethyl- Th esultsatesumma iaesijn thefgl pwi s Tablell.

TABLE 12.NH.0H,-0 0 O-Aryl Example I N o. Aryl Yi Salt V M.p. C.) (percent) 0 H N H01 240 (d ec.) 64. 72 5. 77 5. 53

Elementary analysis (found) 1d Elementary analysis (found) Exam p10 Y N o. Aryl Salt M.p. C (percent) H N 77. Q 01 H 01 255 (dec.) 79 56. 89 4. 47 4. 67

78 C111 11 Cl 203-205 78 62.99 6.12 5.

y rn 0.

79 CH3 H01 220 (dec.) 65. 88 6.08 4. 92

80 O OH; I HCl 176-179 61. 01 5. 50

The following examples A to D show the detailed synthetic procedures for the preparation of some starting compounds usable in the present invention, which are new and have not been disclosed.

Example A trans-4 -N-benzyloxycarbonyl-AMCHA chloride To 6.3 g of trans-AMCHA dissolved in 16 ml of 10 percent aqueous sodium hydroxide solution, 8.2 g of benzyloxycarbonyl chloride and ml of 10 percent aqueous sodium hydroxide solution were added over 15 min., with cooling with ice' water and vigorous stirring. Stirring was continued for 1 hr. The white crystals precipitated were dissolved by adding water and acidified with hydrochloric acid solution with cooling. The white precipitate as formed was collected, washed with water, dried and recrystallized from benzenepetroleumether to have 10.7 g of trans-4-N-benzyloxy-. carbonyl-AMCHA as needles. mp. ll5 -l17 C., yield 92 percent.

Elementary analysis for C l-1 O N (M.W. 291.34):

Calcd. C 65.96, H 7.26, N 4.81

Q B C6 4, 13.3 8.51.07... W. The thus obtained trans-4 benzyloxycarbonyl-AMCHA (5.0 g) was mixed with 5 ml of thionyl chloride and warmed to 40 C. for 30 min. Vigorous reaction took place and a homogenous solution was formed. After cooling, 50 ml of dried petroleum ether was added to the solution to precipitate white crystals, which were collected, washed with dried petroleum ether and dried in vacuo to give4.4 g of trans-4-benzyloxycarbonyl- AMCHA chloride as hygroscopic white crystals melt ing at 77-82 C. (Yield 82 percent).

85-88 C. was obtained from PAMBA. Yield 78.5 percent.

Example B trans-4-N-tertialbutyloxycarbonyl-AMCHA 6 chloride To 47.1 g (0.3 mol) of trans-AMCHA dissolved in 300 ml of 1 N-sodium hydroxide solution and 150 ml of tetrahydrofurane, was added a syrup newly prepared and containing more than 0.33 mol. of tertialbutylcar- .ycarbonyl-AMCHA as white crystalline scales. m.p.

132- 133 C. Yield 58.3 percent.

Elementary analysis for C, H O N (M.W. 257.32):

Calcd. C 59.89, H 8.89, N 5.63

Found C 60.54, H 8.80, N 5.63

The thus obtained trans-4-N-tertbutyloxylcarbonyl- AMCHA (2.3 g) and triethylamine (3.2 g) were dissolved in 40 ml of dried benzene, and to thesolution, purified thionyl chloride (2.4g) was gradually added to have an exothermic reaction with precipitation..The reaction mixture was warmed at 50 C. for 10 min. and then cooled. The precipitate was filtered off, and the filtrate and the washings were combined and concentrated to dryness under reduced pressure to give trans- 4-N-tertbutyloxy-carbonyl-AMCHA chloride as a syrup.

Example C trans-AMCHA chloride Example D @Hydroxy aryl derivatives To a solution of 3.0 g of 4-hydroxyphenylacetic acid in 20 ml of 4 percent aqueous sodium hydroxide and 30 ml of ethanol, 3.0 g of benzylchloride was added and the resulting mixture was heated at reflux on an oil bath 5 at C. for 1.5 hrs. After completion of the reaction,

the ether layer was washed with percent 'aqieBig' ane-l-carboxylate and the pharmaceutically acceptasodium carbonate solution, dried and evaporated. The ble Salts th r fresulting white residue was recrystallized from petrole- 3. 4-carboxymethylphenyl trans-4-aminomethylumether to give 2.3 g of benzyl 4-hydroxypheng I cyci'aiixah i' fbbxyiate and the pharmaceutically ylacetate as white prisms melting at 88-92 C. (Yield 5 acceptable salts thereof.

46.5 percent). 4. 4'-(2"-carboxyethyl)phenyl trans-4-aminomethyl- Elementary. analysis o m u a cyclohexane-l-carboxylate and the pharmaceutically Calcd. C 74.36, H 5.83 acceptable salts thereof. v 4 H Found C 74.51, H594 p l0 5. 4-(2-carboxyvinyl)phenyl trans-4-aminomethyl- In the same manner as above, the following new 4- cyclohexane l-carboxylate and the pharmaceutically hy y yl r i w synt si WM agq p g ql he cqf Wm b Elementary analyses (found; percent) i 1d e p-Hydroxyaryl derivatives ,M.p. C.) (B.p.) C H N (percent) I)HO(CaH4)-CH=CHCOOBZ- 89:91 75.8 37 D-HO(CQH4)'OH1CH:COOBZ 199/1 mm. Hg 75; 1 35 p-HO- (CaH4)CO (CH2)4COOBZ 73. 0 32 I D-HO(CaH4)(CHz)r-COOBZ .--(213.5/1 mm. Hg) 40-41 76.4 37 p-HO-(CaH4)-'CH1-CH(NHCbZ)GOOBz 116J-118 70.3 p-HO'(CH4)-O(OH1)1COOBZ (200-201/1 mm. 70. 4 25. 5

m-HO-(CaHi)-GHz-OHiCOOBz (194-196/1 mm. Hg) 75. 2 6 3 28. 5 2, 4-dibenzyloxyearbonyl phenol- 9183 73. 2 5. 1 29 3benzy1oxycarbonyl-B-naphto1 86-87 76. 1 5. 3 37 6-benzylbxycarbonyl-a-pyrldinolhydrochloride 142-145 (dec.) 58. 4 4. 6 5 6 16 B2: Benzyl radical Obz: Benzyloxycarbonyl radical What we claim is: I 6. 4-(2"-carboxyethoxy )phenyl trans-4- l. A compound of the general formula aminomethyl-cyclohexane-l'carboxylate and the pharmaceutically acceptable salts thereof.

aminomethyl-cyclohexane-l-carboxylate and the pharmaceutically acceptable salts thereof.

hydrmty-S '-carboxy-n-pentyl)phenyl trans-4-aminomethylcyclohexane-l-carboxylate and the pharmaceutically acceptable salts thereof.

wherein Aryl is a phenyl, which may have one to three substituents selected from hydroxy, halogen, nitro, amino, carboxyl,'formyl, sulfamoyl, carboxyalkylamino, C, to C -alkyl, C to C -alkyl, C to C -alkoxl-0xo-5' carbOXy-n-IJM Y )P l' y, (3 t C lk h l, -b lk carboxyap ammornethylcyclohexane-l-carboxylate and the pharkenyl, carboxyalkylcarbonyl, hydroxyalkyl, alkoxycarmaceutlcany accePtable Salts bonyl and carboxyalkyl the alkyl portion of which may 40 yc y )p y be substituted with amino, hydroxy or halogen, and the aminomethylcyclohexane-l-carboxylate and the pharpharmaceuticallyacceptable salts thereof. maceutically acceptable salts thereof.

2. 4-carboxyphenyl transf-aminomethylcyclohe t v H a: 

2. 4''-carboxyphenyl trans-4-aminomethylcyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 3. 4''-carboxymethylphenyl trans-4-aminomethyl-cyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 4. 4''-(2''''-carboxyethyl)phenyl trans-4-aminomethyl-cyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 5. 4''-(2''''-carboxyvinyl)phenyl trans-4-aminomethyl-cyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 6. 4''-(2''''-carboxyethoxy)phenyl trans-4-aminomethyl-cyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 7. 4''-(5''''-carboxy-n-pentyl)phenyl trans-4-aminomethyl-cyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 8. 4''-(1''''-hydroxy-5''''-carboxy-n-pentyl)phenyl trans-4-aminomethylcyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 9. 4''-(1''''-oxo-5''''-carboxy-n-pentyl)phenyl trans-4-aminomethylcyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof.
 10. 4''-(2''''-amino-2''''-carboxyethyl)phenyl trans-4-aminomethylcyclohexane-1-carboxylate and the pharmaceutically acceptable salts thereof. 